“We Are All Mutants”: Mutation Basics

In The Ancestor’s Tale: A Pilgrimage to the Dawn of Evolution (2016), Richard Dawkins writes:

The word ‘mutation’ conjures up images of grotesquely distorted creatures, perhaps generated by unscrupulous experimenters, or springing up as a consequence of some radioactive catastrophe. The truth is somewhat different. We are all mutants. The DNA passed on to us from our parents contains novel changes—mutations—which were not present in the DNA that they inherited from their parents. Fortunately so, for mutations provide the raw material, sculpted over millennia by natural selection, used to build the bodies of all the pilgrims on our journey. (126)

I’ve wanted to understand the basics of such a process that provides the “raw material” for evolution as well as a share of diseases and disabilities.  Explaining it here is a step in that direction, so here’s my version of Mutation Made Simple—very simple. I’ve omitted RNA, base pairs, and gene recombination, and I’ve compressed and approximated.

Such simplification notwithstanding, though, the basics of mutations can be difficult to grasp at first for two reasons. One is that DNA duplication, even when it is on track, takes place in several steps that are difficult to visualize and with four kinds of chemical players of whom three bear names unfamiliar to many people. They are nucleotide, codon, and amino acid; the familiar fourth one is protein. Many mutations start with a miscopied nucleotide, which leads to an error in a codon, which corresponds to the wrong amino acid, which may screw up the protein. Such a chain of effects is a lot to wrap one’s head around.

The second difficulty is that there is “slack” in these steps. That is, many of the missteps that could lead to an actual difference in a body are corrected by the cell or produce no  result or produce a result that is harmless. A kind of built-in “forgiveness factor” prevents every single mistake in DNA copying from invariably leading to potentially risky changes in an organism. Such a buffer in the genetic system is part of its complexity.

dna and codons (www2.le.ac.uk)

From the top: the double strand of DNA; the three-letter codons from one of the strands; and the necklace of amino acids designated by each codon. (www2.le.ac.uk)

That said, let’s look at the normal duplication sequence. Mutations exist because cells require replacement. The first step in making a new cell is for the old one to make a copy of its DNA. DNA strands themselves consist of a line-up of basic organic molecules, the nucleotides. There are only four nucleotides, with names that are abbreviated simply A, C, G, and T. This is the DNA “code,” like the dots and dashes in Morse code.

The cell reads the nucleotides in groups of three. That is, the nucleotides constitute a kind of small alphabet that spells out a vocabulary of 64 three-letter “words.”  Each word or triplet, which is the codon, designates one of twenty amino acids.  (So here is one “slack” point: twenty amino acids designated by three times as many codons means each amino acid may be designated by not just one codon but by several. An incorrect codon doesn’t necessarily call up the wrong amino acid. )

Cells then build the protein molecules that will form the new cell by reading each codon in turn, bringing the appropriate amino acid molecule into place, and stringing it like a bead on a necklace in the proper sequence. The finished molecule, the necklace of amino acids, is a particular and complex protein.

But sometimes over billions of nucleotide duplications, a nucleotide miscopies; what should be a copy of an A is a T instead, a C miscopies as a G.

sickle cell (sicklecellanaemia.org)
Sickle cells among normal red blood cells. (sicklecellanemia.org)

Take the codon TTC, for example. Let’s say that a copy of it comes out as TTA instead, one letter off. When this TTA later comes up in the protein production line, which amino acid does it designate and what will the impact be? Is TTA one of the few “nonsense” codons that match no amino acid all and stop the copying process before the protein is complete? Or, if it does result in a changed protein and gene, will the change be limited to one organism, or has the error occurred in a gene for sperm or the ovum that will carry it to offspring?

Point mutation (Pinterest)

The GAG codon, when it miscopies as GTG, puts into the hemoglobin protein an amino acid that creates sickle-shaped cells can bring on painful anemia but also protection against malaria. (Pinterest)

TTA, it turns out, has no such harsh consequences. The amino acid it calls up has the same function as the one that the original TTC corresponded to. The final protein functions normally. No harm, no foul—another example of “forgiveness” in the replication process. But see the illustrations for the much less neutral mutation that produces Sickle cells in the blood.

Besides such mutations that start with the miscopying of a nucleotide, mutations can also occur in another way: through the insertion or deletion of nucleotides and codons, sometimes one codon, sometimes hundreds.

Codons are read in threes. So the insertion or deletion of even a single nucleotide changes all the codons coming after it in what’s called the frame of the gene, the full sequence of codons. To see the effect, delete just the first letter, t, from this sentence of three-letter words:  “the man won the bet” becomes “hem anw ont heb et…”.  And like such a small deletion, the insertion of a nucleotide has the same chaotic effect.

In other mutations, a codon or group of codons repeats far in excess of the usual number. A gene for brain development, for example, includes from six to fifty repetitions of a CGG codon. That’s normal for that gene. But in a mutation that leads to a form of retardation called Fragile-X Syndrome, the gene repeats the CGG codon from 200 to 1000 times.

So mutations start with nucleotides and codons but may end by altering genes. Some changes are disastrous, some have little or no effect, some are passed on through generations, most are not passed on at all. But in the background, behind the grim or helpful outcomes, mutations keep bringing forth a trickle of variations of all sorts, in all species—the modest but persistent originality of organic life itself. Untypical coloration in an insect or a flower or an animal’s fur may start out as a minor difference. But over generations, if the individuals with the coloring are a little healthier, evade more predators, attract more mates, or produce more offspring, the color mutation will take its place in the species.

 

People Are Different

One perception of mine that has strengthened over the years is how different people are. When I was young, I thought of these differences mostly because of the difficulties they presented—how to talk to this girl, how to respond to a teacher, how to put up with a tedious relative. But after enough time it’s easier to sit back and enjoy the variations. People are a circus of performances, each of us with different things to say, different knacks and loves, different hostilities and indifferences, different politics, different ideas about big issues. The people we know the best, our closest friends and family, are different from each other in ways that we peer into more and more deeply over time. Even the youngest siblings, peas from the same pod, amaze their parents with their dissimilarity.

British marathoners (marathons-event.com)

British marathoners
(marathons-event.com)

I asked a friend who is a therapist how he kept all his patients straight if he didn’t take notes. He said, “You know a lot of people. Do you ever get them mixed up?” We’re good at keeping people sorted out.  We get along with most of them, we love some, and we try to forgive a few. We all understand that the differences among us are serious business because they determine how our lives will play out, and that how a life plays out will create more differences.

Compared to the richness of differences, the similarities among us sometimes seem few and familiar.  As people like to say, down deep we’re all the same. Our common needs and fears are relatively small in number. They’re emotional and biological.  We learn them profoundly and intensely but narrowly. They do justify the amazing claim that all people are created equal and endowed with the same rights. But day to day our brains track not the sameness among people but our differences as we look for signs of who we might connect to. We start at infancy, reading Mom’s face.

We gave up being identical a couple of billion years ago when our bacterial ancestors ceased cloning themselves and instead began mixing up their DNA through sex. Since then, diversity has been natural selection’s ace in the hole; if one combination of genes proves vulnerable, another might solve the problem. Humans have taken the generating of diversity a step further. In addition to the DNA variations, we have a brain inclined toward language, specialization, and complexity. The result is Nancy, Bill, Brett, Joanne, Florence, Ravi, Mike, Meredith, Doris, Kevin, Sandra….